The amino acid, glutamate is the major excitatory neurotransmitter in the central and peripheral nervous system and exerts its effects mainly through ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The mGluRs are seven-transmembrane helix G protein-coupled receptors (GPCRs). The eight known members of the mGluR family are divided into three sub-groups (i.e., Groups I, II, and III) based on sequence homology, signal transduction and pharmacology. mGluR1 and mGluR5 belong to Group I, mGluR2 and mGluR3 belong to Group II, and mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group III.
The orthosteric binding site of the mGluRs, which consists of a large bi-lobed extracellular amino terminal domain, is highly conserved, particularly within each group. For this reason it has been difficult to develop subtype-specific ligands (agonists and antagonists) for these receptors. Recently, advances have been made to develop highly selective compounds which modulate the activity of these receptors by binding within the receptors transmembrane heptahelical domain. These allosteric modulators are compounds that bind receptors at a non-active or non-orthosteric site and thereby can modulate receptor function even if the endogenous ligand is also bound to the receptor (orthosteric site). As a result, an allosteric modulator does not have to compete with the ligand to impact the receptor's function and permits a different approach to designing receptor modulators. As an example, the binding of an allosteric modulator may have a lower affinity to the site and still be effective unlike most conventional antagonists that must block ligand-receptor interactions. Moreover, the modulation of the allosteric site permits the natural processes of the endogenous ligand and associated receptor to continue. One type of allosteric modulator is a negative allosteric modulator (NAM) in which the modulator acts to decrease the signal sent by the endogenous ligand via the receptor. Another type of modulator is the positive allosteric modulator (PAM) which does not exhibit intrinsic agonism of the receptor but facilitates or potentiates agonist-mediated receptor activity. In some instances the modulator may be classified as an allosteric agonist in that it alone, without the effects of the natural ligand, induces receptor activity.
The GPCR contains two distinct domains; a large extracellular domain which binds glutamate at the orthosteric binding site and a heptahelical transmembrane domain, which has been found to bind a variety of ligands at one or more allosteric binding sites. Recent experimental findings show that GPCRs, form homodimers, heterodimers and in some cases hetero-oligomers with members of their own class as well as with other unrelated GPCRs and impacts their trafficking, signaling, and pharmacology (Milligan Drug Discov Today 2006, 11(11-12): 541-549). Although a GPCR monomer is sufficient to activiate a G protein, it is believed that dimerization leads to stabilization of the active conformation and enhancement of G protein activation. It has been clearly established that mGluRs exist as constitutive dimers with the two subunits being linked by a disulfide bridge (Romano et al. J Biol Chem 1996, 271(45):28612-28616). Recent studies have found that activation or inhibition of either monomer of the dimer complex facilitates a change in the activity or function of the adjoining monomer. As an example, it was found that Gi/o protein regulation, which is necessary for the effects of hallucinogens, is enhanced by the formation of the 5HT2A/mGluR2 dimer complex and that activation of the mGluR2 monomer suppresses hallucinogen-specific signaling, while by contrast, the affinity of mGluR2/3 agonists was reduced in the presence of an hallucinogen (Gonzalez-Maeso et al. Nature 2008, 452(7183):93-97).
The neuropsychological effects of hallucinogens present commonalities with the psychosis of schizophrenia, and both conditions are accompanied by disruptions of cortical sensory processing. Comparing the densities of 5HT2A and mGluR2/3 binding sites in the cortex of schizophrenic subjects and controls, it was found that schizophrenic subjects had increased 5HT2A and reduced mGluR2/3 receptor levels. It was found through mRNA assays that expression of mGluR2, but not mGluR3, was reduced in the cortex of schizophrenic subjects (Gonzalez-Maeso et al. Nature 2008, 452(7183):93-97).
Other various CNS disorders have been associated with the mGluR2 and/or mGluR3 receptors, and specific modulators of such receptors might be effective in the treatment of these acute and chronic diseases and conditions. Such acute and chronic diseases and conditions include Alzheimer's disease (Kim et al., J. Neurosci. 2010, 30:3870; Caraci et al., Mol Pharmacol. 2011, 79, 618), schizophrenia (Patil et al., Nature Med 2007, 13:1102), Parkinson's disease (Samadi et al., J. Neuropathol. Exp. Neurol 2009, 68:374), anxiety (Yoshimizu et al., Psychopharmacology 2006; 186:587-593), depression (Yoshimizu et al., Psychopharmacology 2006; 186:587-5930), obsessive-compulsive disorders, addiction (Beveridge et al., Neurosci Letts 2011, in press; Baptista et al J. Neurosci 2004, 33:4723; Dhanya et al., J. Med. Chem, 2011, 54:342; Tsunoka et al Prog. Neuropsychopharmacol Biol Psychiatry 2010, 34:639), epilepsy (Kinon et al., J. Clin Psychopharmacol 2011, 31:349), insomnia (Kinon et al., J. Clin. Psychopharmacol. 2011; 31 (3):349-355; Supplemental Table SDC3), peripheral pain (Carlton et al., Brain Res 2009, 1248:86; Zhang et al., Brain Res. Bulletin 2009, 79:219-223), and cognitive and/or memory deficiencies due to diseases or aging, and the like (Nikiforuk et al., JPET 2010, 335:665). The efficacious treatment of such diseases may be through the activation or inhibition of the glutamate binding site or through a process regulating the activity of the mGluR2 and/or mGluR3 such as by an allosteric modulator. Antagonism of the mGluR2 and/or mGluR3 receptor may also prove beneficial as a therapy for treatment resistant depression, as orthosteric antagonists have been shown to activate the mTOR signaling pathway similar to the downstream effects of a subanesthetic dose of ketamine thus enabling synaptic plasticity (Karasawa et al., Brain Res. 2005, 1042(1): 92-98; Li et al., Science 2010, 329 (5994): 959-964; Koike et al., Neuropharm. 2011, 61(8):1419-1423; Dwyer et al., Int. J. Neuropsychopharmacol. 2012, 15(4):429-434). Other disorders and conditions associated with metabotropic glutamate receptors are cancers directly or indirectly linked to mGluR2/3, including but not limited to glioblastoma (D'Inofrio et al., J. Neurochem 2003, 84:1288-1295; Arcella et al., Neuro-Oncology 2005, 7:236-245), melanoma (Prickett et al., Nature Genetics 2011, 43:1119-1126), colon cancer, esophageal cancer (Chattopadhyay et al., Oncology Reports 2009, 21:1135-1146), pancreatic cancer and breast cancer.
The efficacious treatment of such diseases may be through the activation or inhibition of the glutamate binding site or through a process regulating the activity of the mGluR2 and/or mGluR3 such as by an allosteric modulator. Antagonism of the mGluR2 and/or mGluR3 receptor may also prove beneficial as a more rapid treatment for major depressive disorder and a therapy for treatment resistant depression, as orthosteric antagonists have been shown to activate the mTOR signaling pathway similar to the downstream effects of a subanesthetic dose of ketamine thus enabling synaptic plasticity (Karasawa et al., Brain Res. 2005, 1042(1): 92-98; Li et al., Science 2010, 329 (5994): 959-964; Koike et al., Neuropharm. 2011, 61(8):1419-1423; Dwyer et al., Int. J. Neuropsychopharmacol. 2012, 15(4):429-434).
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.
A need still exists for new drug therapies having greater receptor selectivity for the treatment of subjects suffering from or susceptible to the above diseases, disorders or conditions. In particular, a need still exists for new drugs having one or more improved properties either alone or when combined with other agents (such as safety profile, efficacy, or physical properties) relative to those therapies currently available.